Racemic separation of ketamine

ABSTRACT

The present invention is concerned with an improved process for the resolution of racemic 2-(o-chlorophenyl)-2-methylaminocyclohexanone (ketamine).

This application is a 371 of PCT/EP97/02360 filed May 7, 1997.

DESCRIPTION

The present invention concerns an improved process for the resolution ofracemic 2-(o-chlorophenyl)-2-methylaminocyclohexanone (ketamine).

Pharmacological investigations show clear qualitative and quantitativedifferences between the R- and S-ketamine enantiomers. Not onlypreclinically but also in a clinical study, S-ketamine always behavesbetter than the antipode or the racemate. From these points of view, theexclusive therapeutic use of the enantiomer is to be preferred, as tothe resolution of the racemate. Therefore, in the following, theS-enantomer is always meant which as salt is present in theS-(+)-configuration and as pure base in the S-(-)-configuration.

From German published specification DE-A-2 062 620 is known a processfor the resolution of racemic2-(o-chlorophenyl)-2-methylaminocyclohexanone in which racemic2-(o-chlorophenyl)-2-methylaminocyclohexanone is reacted with the use ofan enantiomeric form of tartaric acid in a solvent mixture of water andacetone, the tartaric acid salt formed is isolated by filtration andsubsequent double recrystallisation with acetonitrile, whereupon oneisomer is liberated from the tartaric acid salt by reaction with alkali.However, the process suffers from poor yields, the use of toxicsolvents, impure products and the necessity of having to carry out manyprocess steps.

Therefore, it was the task of the present invention to provide animproved process for the resolution of racemic2-(o-chlorophenyl)-2-methylaminocyclohexanone in which the abovedifficulties do not occur.

Consequently, the subject of the present invention is a process for theresolution of racemic 2-(o-chlorophenyl)-2-methylaminocyclohexanone ofthe formula: ##STR1## wherein * signifies an asymmetrical carbon atom,which comprises the following steps:

1) reaction of racemic 2-(o-chlorophenyl)-2-methylaminocyclohexanonewith an enantiomeric form of tartaric acid,

2) isolation of the formed tartaric acid salt of2-(o-chlorophenyl)-2-methylaminocyclohexanone and

3) reaction of the isolated tartaric acid salt of2-(o-chlorophenyl)-2-methylaminocyclohexanone with alkali, whereby anisomer of 2-(o-chlorophenyl)-2-methylaminocyclohexanone can be isolated,

whereby steps 1 and 2 are carried out in water or a mixture of water andan alcohol and/or ketone, ether or ester. ##STR2##

In the scope of the process according to the present invention, racemic2-(o-chlorophenyl)-2-methylaminocyclohexanone is reacted in a first stepwith an enantiorneric form of tartaric acid with the formation of atartaric acid salt of 2-(o-chlorophenyl)-2-methylaminocyclohexanone. Assolvent in this reaction, there are used water or a mixture of water andan organic solvent selected from the group consisting ofstraight-chained or branched C₁ -C₆ -alcohols and/or ketones, esters orethers, preferably isopropanol and/or acetone. Water or a mixture ofwater and isopropanol or a mixture of water or acetone is preferablyused. In the case of using a mixture of water and isopropanol, the ratioof water:isopropanol is preferably 1.5:1. In the case of using a mixtureof water and acetone, the ratio of water:acetone is preferably1:0.33-5.0 and especially 1:3. Other organic solvents which can also beconsidered include, for example, methanol, ethanol, n-propanol, butanol,t-butanol, pentanol, hexanol, methyl ethyl ketone, dimethyl ketone,propyl methyl ketone and/or ethyl acetate.

In a second step, the formed tartaric acid salt of2-(o-chlorophenyl)-2-methylaminocyclohexanone is isolated, thispreferably taking place by filtration. In the case of using a mixture ofwater and acetone in a ratio of 1:10-20, the tartaric acid salt formedis, preferably after an isolation for the further enrichment of anenriched tartrate of an isomer of2-(o-chlorophenyl)-2-methylaminocyclohexanone from the solvent mixtureused in step, recrystallised from water and acetone. In the case of theuse of water or of a mixture of water and isopropanol or of a mixture ofwater and acetone in a ratio of 1:0.33-5.0 as solvent, arecrystallisation of the isolated tartaric acid salt of2-(o-chlorophenyl)-2-methylaminocyclohexanone can be omitted.

In the third step, the tartrate of2-(o-chloro-phenyl)-2-methylaminocyclohexanone obtained in step 2 isreacted with alkali, a crystalline product thereby being obtained, thisbeing an isomer-pure 2-(o-chloro-phenyl)-2-methylaminocyclohexanone.This can be obtained, for example, by filtration.

Subsequently, the isomer-pure ketamine can be converted withhydrochloric acid into the corresponding hydrochloride.

In the following, the present invention is further illustrated on thebasis of examples. It is to be understood that the examples in no waylimit the scope of the present invention.

EXAMPLE 1

50 g (0.21 mol) R,S-ketamine are dissolved in 613 ml of acetone at theboiling point and subsequently mixed with 31.5 g (0.21 mol)L-(+)-tartaric acid. In order to obtain a clear solution, 40 ml of waterare added thereto at the boiling point and subsequently the clearsolution is filtered off while still hot. After the addition of seedcrystals obtained in a small preliminary experiment, the whole isallowed to cool to ambient temperature while stirring. After standingovernight, the crystals formed are filtered off with suction and driedin a circulating air drying cabinet (first at ambient temperature andthen at 50-60° C.).

Yield (tartrate): 64.8 g

m.p.: 161° C.

[α]_(D) : +26.1° (c=2/H₂ O)

Thereafter, the crystallisate is recrystallised in a mixture of 1226 mlacetone and 90 ml water. After cooling to ambient temperature andsubsequently stirring for 4 hours, the crystals are filtered off withsuction and dried in a circulating air drying cabinet (first at ambienttemperature and then at 50-60° C). There are obtained 38.8 g of tartrate(95.29% of theory).

m.p.: 175.3° C.

[α]_(D) : +68.9° (c=2/H₂ O)

The base is liberated by taking up 38.8 g of tartrate in 420 ml ofaqueous sodium hydroxide solution and stirring with 540 ml of diethylether. The ethereal phase is first washed with water and subsequentlywith a saturated solution of sodium chloride. The organic phase is driedover anhydrous sodium sulphate. After filtering, the solution isevaporated to dryness on a rotary evaporator, a crystalline, colourlessproduct remaining behind.

Yield (crude base): 21.5 g=86.0% of theory

m.p.: 118.9° C. (literature: 120-122° C.)

[α]_(D) : -55.8° (c=2/EtOH) (literature: [α]_(D) : -56.35° ).

In order possibly to achieve a further purification, the base can berecrystallised from cyclohexane. For this purpose, 10.75 g of the crudebase are dissolved in 43 ml cyclohexane at the boiling point. Whilestirring, the clear solution is slowly cooled to about 10° C. and thenstirred at this temperature for about 1 hour. The crystallisate whichprecipitates out is filtered off with suction and dried to constantweight.

Yield (base): 10.3 g=82.4% of theory

m.p.: 120° C. (literature: 120-122° C.)

[α]_(D) : -56.8° (c=2/EtOH) (literature: [α]_(D) : -56.35° )

EXAMPLE 2

125 ml of water are taken and subsequently 31.5 g (0.21 mol)L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine added thereto.While stirring, this mixture is warmed to 50-60° C. until a clearsolution results. After cooling to ambient temperature while stirringand subsequently stirring overnight, the crystals formed are filteredoff with suction. Subsequently, the crystallisate is first washed withwater (1-6° C.) and subsequently washed twice with, in each case, 20 mlof acetone. Drying in a circulating air drying cabinet (first at ambienttemperature and then at 50-60° C.) gives 31.79 g of tartrate (78.23%) oftheory).

EXAMPLE 3

150 ml of water are taken and subsequently mixed with 39.8 g (0.27 mol)L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine. While stirring,this mixture is warmed to 50-60° C. until a clear solution results.

After cooling to ambient temperature while stirring and subsequentlystirring overnight, the crystals formed are filtered off with suction.Subsequently, the crystallisate is successively washed with 8 ml ofwater (1-6° C.) and thereafter twice with, in each case, 20 ml acetone.

Drying in a circulating air drying cabinet (first at ambient temperatureand then at 50-60° C.) gives 32.58 g of tartrate (80.02% of theory).

EXAMPLE 4

150 ml of water and 50 ml isopropanol are taken. After the addition of39.8 g (0.21 mol) L-(+)-tartaric acid and 50 g (0.21 mol) R,S-ketamine,the mixture is heated to reflux temperature while stirring until asolution results (possibly add water until all is dissolved).

Subsequently, while stirring, the solution is allowed to cool to ambienttemperature and stirred overnight. The crystals are filtered off withsuction and subsequently washed with a 1:2 mixture of 20 ml ofwater/isopropanol and dried in a circulating air drying cabinet (firstat ambient temperature and then at 50-60° C.). There are obtained 24.45g of tartrate (62.63% of theory).

EXAMPLE 5

50 g (0.21 mol) R,S-ketamine are dissolved at the boiling point in 300ml acetone and subsequently mixed with 31.5 g (0.21 mol) L-(+)-tartaricacid and 100 ml of water. The whole is allowed to cool while stirringand possibly seeded.

After standing overnight, the crystals formed are filtered off withsuction, then washed twice with, in each case, 20 ml acetone and driedin a circulating air drying cabinet (first at ambient temperature andthen at 50-60° C.). There are obtained 30.30 g of tartrate (74.57% oftheory).

EXAMPLE 6

75 ml of water and 50 ml isopropanol are taken and subsequently 39.8 g(0.27 mol) L-(+)-tartaric acid added thereto. While stirring, themixture is heated to reflux temperature until a clear solution results.After cooling to ambient temperature while stirring and subsequentlystirring overnight, the crystals formed are filtered off with suction.Subsequently, the crystallisate is washed with a 1:2 mixture of 20 mlwater/isopropanol. After drying in a circulating air drying cabinet(first at ambient temperature and then at 50-60° C.), there are obtained34.84 g of tartrate (85.74% of theory).

EXAMPLE 7

20 g of the S-(+)-tartrate obtained in Example 4 are dissolved in 100 mlof water at 30-40° C. With about 7 ml of 50% sodium hydroxide solution,an S-(-)-ketamine base is precipitated out up to about pH 13. It isfiltered off with suction and washed neutral with water to pH 7-8.Subsequently, it is dried for about 24 hours at 50° C. in a circulatingair drying cabinet. There are obtained 11.93 g S-(-)-ketamine (97.79% oftheory).

EXAMPLE 8

5 g of the S-(-)-ketamine obtained in Example 7 are dissolved in 50 mlisopropanol at about 50° C. and possibly filtered off with suction overkieselguhr. Subsequently, gaseous hydrogen chloride is passed in at50-60° C. until a pH value of 0-1 is reached. The reaction mixture isallowed to cool to ambient temperature, filtered off with suction andwashed with about 5 ml isopropanol. The moist product is dried overnightat about 50° C. in a circulating air drying cabinet. There are obtained5.09 g S-(+)-ketamine hydrochloride (88.06% of theory).

We claim:
 1. Process for the resolution of racemic2-(o-chlorophenyl)-2-methylaminocyclohexanone of the formula: ##STR3##wherein * is an asymmetric carbon atom, which comprises the followingsteps:1) reaction of racemic2-(o-chlorophenyl)-2-methylaminocyclohexanone with an enantiomeric formof tartaric acid, 2) isolation of the formed tartaric acid salt of2-(o-chlorophenyl)-2-methylaminocyclohexanone and 3) reaction of theisolated tartaric acid salt of2-(o-chlorophenyl)-2-methylaminocyclohexanone with an alkali, whereby anisomer of 2-(o-chlorophenyl)-2-methylaminocyclohexanone can beisolated,wherein steps 1 and 2 are carried out in water or in a mixtureof water and an alcohol and/or ketone, ether or ester.
 2. Processaccording to claim 1, wherein the solvent in step 1 and step 2 is wateror a mixture of water and isopropanol and/or acetone.
 3. Processaccording to claim 1, wherein the solvent in step 1 and step 2 is water.4. Process according to claim 1, wherein the solvent in step 1 and step2 is a mixture of water and isopropanol.
 5. Process according to claim4, wherein the ratio of water:isopropanol is 1.5:1.
 6. Process accordingto any of the preceding claims, wherein an aqueous solution of sodiumhydroxide is used as alkali.
 7. Process according to claim 1, whereinthe free isomer obtained of2-(o-chlorophenyl)-2-methylaminocyclohexanone is subsequently convertedinto the hydrochloride salt of the isomer in question by reaction withhydrochloric acid.
 8. Process according to claim 1, wherein the ratio ofwater:acetone is in the range of 1:0.3-5.0.
 9. Process according toclaim 1, wherein the ratio of water:acetone is in the range of 1:3. 10.Process according to claim 1, wherein the ratio of water:acetone is inthe range of 1:10-20.
 11. Process according to claim 1, wherein thetartaric acid salt of 2-(o-chlorophenyl)-2-methylaminocyclohexanoneisolated in step 2 is reacted directly in step 3 without subsequentrecrystallisation.
 12. Process according to claim 9, wherein thetartaric acid salt of 2-(o-chlorophenyl)-2-methylaminocyclohexanoneisolated in step 2 is recrystallised before carrying out step 3.